Orally administrable immediate-release and prolonged-release galenic form comprising an absorption-promoting agent and use of this absorption-promoting agent

ABSTRACT

The present invention relates to an orally administrable galenic form allowing improved absorption by the transmembrane or paracellular route in the gastrointestinal tract of active ingredients which are hydrophilic or ionizable in physiol. media, comprising at least one such active ingredient, an absorption-promoting agent having an HLB&gt;8, the the absorption-promoting agent consisting of one or more lipid substances chosen from: polysorbates; polyoxyethylene ethers; esters of polyoxyethylene and fatty acids; fatty acids; fatty alcs.; bile acids and their salts with pharmaceutically acceptable cations; esters of C1-C6 alkanol with fatty acids; esters of polyol with fatty acids, the polyol comprising from 2 to 6 hydroxyl functional groups; and polyglycolyzed glycerides; in combination with one or more pharmaceutically acceptable excipients, the pharmaceutical forms comprising captopril being excluded. A controlled-release tablet contained (1) cores contg. calcium acamprosate 50, Gelucire 44/14 10, Compritol 10, microcryst. cellulose 19, Povidone 10, and Mg stearate 1% and (2) a film-coating compn. contg. HPMC 64, PEG-4000 15, and talc 21%.

This application is a 371 of PCT/EP99/00994 filed Feb. 16,1999.

The invention relates to orally administrable galenic forms comprisingone or more active ingredients which are hydrophilic or ionizable inphysiological media in combination with one or more excipients. Thesegalenic forms are preferably solid forms such as tablets or gelatincapsules. The galenic compositions of the invention are particularlyadvantageous in that they allow improved absorption of activeingredients which are hydrophilic and/or ionizable in physiologicalmedia, by the transmembrane or paracellular route, because of theirparticular excipient composition.

The absorption of orally administered active ingredients essentiallytakes place by the transmembrane or paracellular route at the level ofthe mucous membranes of the gastrointestinal tract. In the case ofactive ingredients which are hydrophilic or ionizable in physiologicalmedia, the absorption predominantly takes place by the paracellularroute. Because of this, the bioavailability of this type of activeingredient is very low, the kinetics of absorption being very slow.Numerous authors have more precisely studied the kinetics of absorptionof active ingredients in the form of calcium salts and have observedthat the transport of these substances by the paracellular route is verylimited: it appears that the calcium salts have the effect of closingagain the channels present between the cells which provide for transportby the paracellular route. Reference may be made, for example, to P.Artursson and C. Magnusson, J. Pharm. Sci., 79, 595, 1990 and S. G.Milton and V. P. Knutson, J. Cell. Physiol., 144, 498, 1990.

The use of various excipient systems comprising liquid or amphiphiliccompounds such as semisynthetic glycerides for promoting the absorptionof active substances has been abundantly illustrated in the art. In thisregard, there may be mentioned the following state of the art documents:WO 93/00891, EP 670 166, WO 95/08 983, WO 94/23 733 and WO 96/21 439.All the prior art formulations are intended, however, to improve thebioavailability of lipophilic active substances. Moreover, theformulations provided in the case of tablets, granules or microgranulesdo not always allow control of the kinetics of release.

This may result in an intense increase in the plasma concentration,which is quite often followed, in the case of compounds having a shorthalf-life, by a rapid decrease in these levels which reach values belowthe therapeutic threshold. Multiplication of the number of doses is thennecessary in order to maintain a therapeutic effect for the medication.

However, control of the absorption of the active ingredients at thelevel of the gastrointestinal tract will ensure the efficacy of thetherapy used. Furthermore, modulation of the release (while preservingan optimized absorption) makes it possible to ensure better therapeuticcover and to improve tolerance and compliance. Thus, it is possible toreduce the number of doses of the medicament and to thereby ensurecompliance with the treatment. This is essential in the case oftreatment of long-term, or even chronic, disorders or pathologies.

The galenic forms of the invention allow improvement in the absorptionof the active ingredients which are hydrophilic and/or ionizable inphysiological media, the control of the kinetics of release and themaintenance of the yield of absorption, this being also in the case ofsolid pharmaceutical forms such as tablets, gelatin capsules ormicrogranules.

Although the galenic forms of the invention are particularly appropriatefor the administration of active substances which are hydrophilic and/orionizable in physiological media, they are also suitable for theadministration of lipophilic substances.

It may also be noted that the pharmaceutical dosage forms of theinvention ensure excellent reproducibility of the results, whileallowing increased control of the rate of release during the phase ofprolonged release of the active ingredient. By using the pharmaceuticaldosage forms of the invention, it becomes possible to optimize theavailability of the active ingredients in the body taking into accountboth the tolerance of the subject to the active ingredient and thepharmacokinetic and metabolic profiles of the active ingredient.

The tablets of the invention are moreover advantageous from the point ofview of the formulation of the active ingredients since a judiciouschoice of the excipients leads to tablets with high concentrations ofactive ingredients.

The invention provides more precisely orally administrable galenic formscomprising an active ingredient which is hydrophilic and/or ionizable inphysiological media, an absorption-promoting agent having an HLB(hydrophilic/lipophilic balance value) greater than 8 and one or morepharmaceutically acceptable excipients.

It should be understood that the galenic forms comprising captopril asactive ingredient are excluded from the subject of the invention.

According to the invention, the absorption-promoting agent consists ofone or more lipid substances chosen from:

polysorbates; ethers of polyoxyethylene and alkyl; esters ofpolyoxyethylene and fatty acids; fatty acids; fatty alcohols; bile acidsand their salts with pharmaceutically acceptable cations; esters ofC₁-C₆ alkanol with fatty acids; esters of polyol with fatty acids, thesaid polyol comprising from 2 to 6 hydroxyl functional groups;polyglycolysed glycerides.

These lipid substances are of natural or synthetic origin, oralternatively are obtained by semisynthesis. A good number of them arecommercially available or are easily prepared from commercial products.

Although the inventors do not intend to be limited to any mechanism ofaction, it is thought that by acting on the surface tension ofbiological fluids, these substances act on membrane contacts at thelevel of the cells of the gastrointestinal mucous membrane. Whatever thecase, it is thought that the absorption-promoting agent creates in situan environment with modified lipophilicity.

The polysorbates are esters of fatty acids of polyethoxylated sorbitan.Polyethoxylated sorbitan offers polyethoxylated sorbitol andpolyethoxylated sorbitol anhydrides. The expression “polysorbate”designates both mono- and polyesters of fatty acids. Preferably, thepolysorbates used according to the invention are mono-, di- or triestersof saturated or unsaturated fatty acids, in which the fatty acids arepreferably C₈-C₂₂, better still C₁₂-C₁₈. There may be mentioned moreparticularly monolaurate, monopalmitate, mono- and tristearate,monooleate and monoisostearate.

Preferably, the polysorbates used are the product of the esterificationof fatty acids with the copolymer of a molecule of sorbitol or of one ofits anhydrides and of 3 to 30 molecules of ethylene oxide.

By way of example, the structural formulae of a monoester and of atriester are given below:

where R is the residue of a fatty acid and x, y, z and w are integerswhose sum varies between 3 and 30, preferably between 4 and 20.

Generally, polysorbates will be used whose molecular weight variesbetween 450 and 2000, better still between 500 and 1900.

Such polysorbates are commercially available, especially under the tradename Tween®.

The ethers of polyoxyethylene and alkyl have the general formula:

CH₃(CH₂)×(OCH₂CH₂)_(y)OH

in which x is an integer between 8 and 22, preferably between 12 and 18,and y is an integer from 10 to 60. Among these compounds, there may bementioned monocetyl ether of polyethylene glycol, monolauryl ether ofpolyethylene glycol, monooleyl ether of polyethylene glycol andmonostearyl ether of polyethylene glycol. These compounds arecommercially available, especially under the trade name Brij®.

The esters of polyoxyethylene and fatty acids are either fatty acidmonoesters of the formula:

RCO—(OCH₂CH₂)_(n)—OH

where R represents the residue of a fatty acid and n the degree ofpolymerization of the polyethoxylated chain,

or fatty acid diesters of formula:

RCO—(OCH₂CH₂)_(n)—OCOR

where R and n are as defined above,

or mixtures of these monoesters and of these diesters. These compoundsare commonly prepared from the corresponding fatty acids andpolyethylene glycols.

The polyethylene glycols used as starting material have variable averagemolecular masses of between 100 and 7000, preferably between 150 and6000. The starting fatty acids are saturated or unsaturated andgenerally have from 8 to 22 carbon atoms, better still from 12 to 18carbon atoms. The esters of polyoxyethylene and fatty acid areespecially marketed by the company AKZO-NOBEL

The fatty alcohols which can be used according to the invention aresaturated or unsaturated, and have preferably from 8 to 22 carbon atoms,better still from 12 to 18 carbon atoms.

The fatty acids are saturated or unsaturated, and have preferably from 8to 22 carbon atoms, or better still from 12 to 18 carbon atoms.

The bile acids are well known to persons skilled in the art. There maybe mentioned glycocholic acid and taurodeoxycholic acid as preferredbile acids. Within the framework of the invention, the promoting agentmay comprise a bile acid salt obtained by reacting this acid with apharmaceutically acceptable base. The salts of alkali and alkaline-earthmetals are particularly advantageous, such as sodium glycocholate.

The esters of C₁-C₆ alkanol with fatty acids can also be used asabsorption-promoting agent. Preferably, the fatty acids leading to theseesters are as defined above.

The polyol esters are obtained by condensation of one or more fattyacids, as defined above, with a polyol comprising 2 to 6 hydroxylfunctional groups. Among these esters, those obtained by esterificationof glycols, polyglycerols, sorbitol or its anhydrides are particularlypreferred. As glycol, propylene glycol may be mentioned.

The esters of sorbitol or of its anhydrides with one or more fatty acidsare fatty acid esters of sorbitan, especially marketed under the trademark Span®.

The polyglycolysed glycerides are mixtures of glycerides of fatty acidsand of esters of polyoxy-ethylene with fatty acids. In these mixtures,the fatty acids are saturated or unsaturated C₈-C₂₂, for example C₈-C₁₂or C₁₆-C₂₀. The glycerides are mono-, bi- or triglycerides or mixturesthereof in any proportions. Polyglycolysed glycerides are marketedespecially by the company Gattefosse under the trade names Labrafil®,Labrasol and Gelucire®.

According to the invention it is essential that the absorption-promotingagent has an HLB greater than 8. Preferably, the HLB is greater than 10;better still it varies between 12 and 16. It should be understood thatwhen the absorption-promoting agent consists of a mixture of severallipid substances, it is the mixture of these substances which shouldhave an HLB greater than 8.

The preferred galenic forms of the invention are those for which theabsorption-promoting agent comprises at least one polyglycolisedglyceride, especially at least one polyglycolysed glyceride having anHLB of between 12 and 16.

Advantageously, the absorption-promoting agent comprises, in combinationwith one or more polyglycolysed glycerides, an ester of sorbitan withone or more fatty acids. By way of illustration, theabsorption-promoting agent consists of a mixture of one or morepolyglycolysed glycerides and a sorbitan ester with a C₈-C22 fatty acid,preferably a C₁₆-C₂₀ fatty acid also having an HLB of between 12 and 16.Among the referred sorbitan esters, there may be mentioned sorbitanmonolaurate, sorbitan trilaurate, sorbitan monoisostearate, sorbitanmonopalmitate, sorbitan monostearate, sorbitan sesqui-isostearate,sorbitan sesqui-oleate, sorbitan trioleate and sorbitan tristearate.

Particularly advantageous examples are:

an absorption promoter consisting of Gélucire® 44/14;

an absorption promoter consisting of a mixture of Gelucire® 44/14 andLabrasol®;

an absorption promoter consisting of a mixture of Gelucire® 44/14,Labrasol® and an ester of sorbitan with a C₁₆-C₂₀ unsaturated fattyacid, such as sorbitan trioleate.

It should be noted that the lipid substances constituting theabsorption-promoting agent may also play the role of lubricant, ofwetting agent, of thickening agent or of plasticizer.

Thus, glyceryl monostearate and glyceryl palmitostearate have a goodlubricating power. Glyceryl monooleate and the fatty acid esters ofpolyethoxylated sorbitan play the role of wetting agent and the C₁₆-C₂₀fatty alcohols and fatty acids (stearic acid, cetyl alcohol), glycerolpalmitostearate and more generally some fatty acid glycerides among themonoglycerides, diglycerides and triglycerides are also thickeners. Inthe same manner, the medium- or short-chain triglycerides act asplasticizers.

Finally, the esters of fatty acid and sorbitan (marketed for exampleunder the name Span®) and the fatty acid esters of polyethoxylatedsorbitan (marketed for example under the name Tween®) can be used asadditives which may be incorporated into the semisolid matrix forfilling gelatin capsules.

The galenic forms of the invention are more particularly intended toimprove the absorption of active ingredients which are hydrophilicand/or ionizable in physiological media corresponding to at least one ofthe following definitions:

(A) active ingredients comprising at least one and generally twofunctional groups chosen from carboxylic acid, sulphonic acid,phosphoric acid, phosphonic acid, phosphinic acid and phenol functionalgroups in free form or ionized form with pharmacologically acceptablecations;

(B) the active ingredients comprising at least one and generally twofunctional groups chosen from the sulphonic acid, phosphoric acid,phosphonic acid and phosphinic acid functional groups in free form orionized form with pharmacologically acceptable cations;

(C) the active ingredients in the form of calcium salts;

(D) the active ingredients which have the formula (I)

 in which

X is chosen from:

R being a C₁-C₇ alkyl radical,

R₁, R₂, R₃ are chosen from hydrogen and a C₁-C₇ alkyl radical,

A represents a group of formula:

with v and w=0, 1, 2

or a group of formula

R₅, R₆ being chosen, independently of each other, from hydrogen, a C₁-C7alkyl radical, an aryl radical having from 6 to 14 carbon atoms and aheteroaryl radical chosen from furyl, thienyl and thiazolyl, it beingpossible for the aryl and heteroaryl radicals to carry 1 to 3substituents chosen from a C₁-C₇ alkyl group, a halogen or atrifluoromethyl group, and t=1-3,

R₄ is chosen from hydrogen, a C₁-C₇ alkyl radical, a CF₃ radical, anaryl radical having from 6 to 14 carbon atoms and a heteroaryl radicalchosen from furyl, thienyl and thiazolyl, it being possible for the aryland heteroaryl radicals to carry 1 to 3 substituents chosen from a C₁-C₇alkyl group, a halogen or a trifluoromethyl group,

M represents a monovalent metal (Na, K, Li) or a divalent metal (Ca, Mg,Sr, Zn),

m=1 or 2,

p=1-2 and q=1-2, p and q being such that the electrical neutrality ofthe salt is ensured.

Among these, the following are particularly preferred:

those for which X=

those for which X=

 the following compounds:

calcium 3-acetylamino-1-propanesulphonate (or calcium acamprosate)

calcium 3-(2-(methyl)propanoylamino)propanesulphonate

magnesium 3-(2-(methyl)propanoylamino)propanesulphonate

calcium 3-(butanoylamino)propanesulphonate

magnesium 3-(butanoylamino)propanesulphonate

calcium 3-(acetylamino)pentanesulphonate

calcium 3-(pentanoylamino)propanesulphonate

calcium 3-(benzoylamino)propanesulphonate

magnesium 3-(benzoylamino)propanesulphonate

strontium 3-(acetylamino)propanesulphonate

zinc 3-(2-(methyl)propanoylamino)propanesulphonate

strontium 3-(2-(methyl)propanoylamino)propanesulphonate

calcium 3-(3-(methyl)propanoylamino)propanesulphonate

magnesium 3-(3-(methyl)butanoylamino)propanesulphonate

calcium 3-(2,2-(dimethyl)propanoylamino)propanesulphonate

magnesium 3-(2,2-(dimethyl)propanoylamino)propanesulphonate

calcium 3-(acetylamino)-2-methylpropanesulphonate

calcium 3-(acetylamino)-3-methylpropanesulphonate

magnesium 3-(acetylamino)-3-methylpropanesulphonate

calcium 3-(acetylamino)-1-methylpropanesulphonate

calcium 3-(acetylamino)-2-phenylpropanesulphonate

calcium 2-(2-acetylaminomethyl)phenylmethanesulphonate

calcium N-(methyl-3-(acetylamino)propanesulphonate

calcium (3-(acetylamino)propyl) ethylphosphinate

calcium 3-(acetylamino)-2-dimethylpropanesulphonate

calcium 3-(trifluoromethylcarbonyl)propanesulphonate;

(E) the active ingredients which are guanidines or guanylguanidines suchas metformin or any one of its pharmaceutically acceptable salts andespecially metformin hydrochloride;

(F) the active ingredients which are pharmaco-logically acceptable saltsof primary, secondary and tertiary amines, such as hydrochlorides,hydrobromides, maleates, acetates, succinates, propionates, fumaratesand oxalates;

(G) the active ingredients which, in free form or ionized form with thepharmacologically acceptable cations or anions present in thephysiological media, have a solubility greater than 100 g, preferablygreater than 250 g per litre;

(H) the active ingredients which, in free form or ionized form with thepharmacologically acceptable cations or anions present in thephysiological media, have a partition coefficient D (octanol/water)corresponding to the relationship log₁₀D<0, preferably log₁₀D<−0.5, orbetter still log₁₀D<−20.

The partition coefficient D is determined in a conventional manner usingthe “shake flask” technique.

A known quantity of product is introduced into a container containingoctanol and water in equal parts (100 ml of water; 100 ml of octanol;the quantity of active ingredient being about 10⁻³ M). The mixture isstirred until the product reaches its equilibrium state between the twophases. The phases are then separated. The product may be assayed inboth phases by various known methods adapted to the nature of the activeingredient (spectrometry, chromatographic techniques) The partitioncoefficient D is given by the equation:

Log D=log (Coct/Caq)

where

Coct: concentration of active ingredient in the octanolic phase;

Caq: concentration of active ingredient in the aqueous phase.

As particularly preferred active ingredients, there may be mentionedmetformin and acamprosate as well as their pharmacologically acceptablesalts.

The pharmacologically acceptable salts are those commonly used in theart. The alkali and alkaline-earth metal salts are examples.

The quantity of active ingredient present in the galenic forms of theinvention varies between 0.001 and 95% by weight, preferably between0.01 and 90%, or better still between 0.1 and 90%.

Depending on the desired effect, persons skilled in the art willincorporate into the galenic compositions of the invention a larger orsmaller quantity of absorption-promoting agent. In the general case, theratio of the active ingredient(s) to the absorption-promoting agent isbetween 0.001 and 10, for example between 0.01 and 10.

The galenic forms of the invention may be provided in a solid form ofthe tablet or gelatin capsule type. When the galenic form is a tablet,the ratio of the active ingredient(s) to the absorption-promoting agentis between 1 and 10.

When the galenic form is a gelatin capsule, the ratio of the activeingredient(s) to the absorption-promoting agent is between 0.1 and 2.

The tablets according to the invention may comprise, in combination withthe absorption-promoting agent, one or more additional excipients so asto obtain mono- or polyphase tablets. Persons skilled in the art willchoose these excipients according to the desired final properties, theapplication envisaged or so as to overcome a disadvantage linked to themethod of manufacturing the tablets.

These excipients exist especially among the following categories:diluents, binders, lubricants, antioxidants, colorants, sweeteners,flavourings and acidulants, wetting agents, hydrophilizing agents suchas sorbitol and cyclodextrins, osmotic agents such as mannitol, pHregulators, stabilizing agents such as trehalose and mannitol,adsorbants, chelating and sequestering agents and gastro-resistantfilm-coating excipients of the type including cellulose acetyl phthalateand polymethacrylates.

By way of example, any one of the following diluents or a combinationthereof may be chosen: calcium carbonate, calcium sulphate, sucrose,dextrates, dextrin, dextrose, dicalcium phosphate dihydrate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, cellulose,microcrystalline cellulose, sorbitol, starches, pregelatinized starch,talc, tricalcium phosphate and lactose.

Among the binders, there may be mentioned: gum arabic, gum tragacanth,guar gum, alginic acid, sodium alginate, sodium carboxymethylcellulose,dextrin, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, liquidglucose, magnesium and aluminium silicate, maltodextrin, povidone,pregelatinized starch, starch and zein.

The lubricants are glidants (such as anhydrous silicate, magnesiumtrisilicate, magnesium silicate, cellulose, starch, talc or tricalciumphosphate) or alternatively antifriction agents (such as calciumstearate, hydrogenated vegetable oils, paraffin, magnesium stearate,polyethylene glycol, sodium benzoate, sodium lauryl sulphate, fumaricacid, stearic acid or zinc stearate and talc).

As examples of antioxidants, persons skilled in the art can select anyof the following compounds: ascorbic acid, ascorbyl palmitate, fumaricacid, propyl gallate, sodium ascorbate and sodium metabisulphite,alpha-tocopherol, malic acid, butylated hydroxytoluene (BHT) andbutylated hydroxyanisol (BHA).

Preferred wetting agents are:

sodium docusate and sodium lauryl sulphate which are anionicsurfactants;

benzalkonium chloride, benzethonium chloride and cetrimide, which arecationic surfactants;

polyvinyl alcohol and sorbitans, which are non-ionic surfactants.

Among the pH regulators, there may be mentioned acidifiers of the typeincluding citric acid, hydrochloric acid, lactic acid, tartaric acid, aswell as alcalinizing agents of the type including monoethanolamine,diethanolamine and triethanolamine, potassium citrate, sodiumbicarbonate, sodium citrate dihydrate.

Examples of adsorbants are bentonite, anhydrous colloidal silica,kaolin, magnesium and aluminium silicate, microcrystalline cellulose andcellulose.

As chelating and sequestering agents, there may be used citric acidmonohydrate, edetic acid, disodium phosphate, monosodium phosphate,potassium citrate, tartaric acid and sodium citrate dihydrate.

The quantities of these additives are those usually used in the art. Ingeneral, the binder may represent from 0.5 to 25% by weight, or betterstill from 2 to 5% by weight of the tablet.

The lubricants are preferably incorporated into this tablet in an amountof 0.01 to 10% by weight.

As a guide, the quantity of gastro-resistant film-coating excipientsvaries between 0.5 and 9% by weight of the tablet.

These tablets may be bare, but are preferably film-coated. Thefilm-coating envisaged will make it possible to avoid an unpleasanttaste by bringing about masking of the taste. It may participate inmodifying the release of the active ingredient and/or of the promotingagent. A gastro-resistant film-coating will make it possible to avoidany release in the stomach; a film-coating which is more hydrophobic andinsensitive to pH variations will contribute more towards extending thekinetics of dissolution. Depending on the role attributed to thefilm-coating, persons skilled in the art will be able to choose thefilm-forming agent from among the following categories: cellulosederivatives such as hydroxypropylmethylcellulose (HPMC), ethylcellulose, cellulose acetophthalate, cellulose acetopropionate,cellulose trimelliate, the polymers and copolymers of methacrylic acidand its derivatives. The film-forming agent may be supplemented with:

plasticizers (such as polyoxyethylene glycols of high molecular weight,esters of polyacids such as citric acid or phthalic acid)

fillers (such as talc, metal oxides such as titanium oxide)

colorants chosen from those usable and approved by the pharmaceuticaland food industries.

The tablets of the invention are conventionally prepared by a methodincluding the steps of granulation followed by compression. Moreprecisely, the method of manufacture which is the subject of theinvention comprises the steps consisting in:

a) preparing a granule of an active substance from a pulverulent mixtureof the active substance, to which there would have been added theabsorption-promoting agent, preferably in liquid form, agents modifyingthe kinetics of dissolution, a binding agent and any other excipientwhich persons skilled in the art will judge to be necessary. The granuleformed is called the inner phase.

b) preparing, where appropriate, a pulverulent mixture, termed outerphase, comprising for example cohesion agents, glidants, lubricants.

c) combining, by mixing, the inner and outer phases. It should be notedthat all of the constituents of the outer phase may be added and mixedwith the excipients of the inner phase during the preparation of thegranule ready to be compressed.

d) forming the tablet by compressing the mixture.

Step (a) involves the granulation of powders of amorphous orcrystallized particles. This granulation is carried out in a mannerknown per se and, for example, by a wet granulation method.

The granulation method comprises five essential steps: (i) dry mixing ofthe various constituents, (ii) wetting, (iii) actual granulation, (iv)drying, and then (v) sizing.

The dry mixing consists of mixing the pulverulent excipients enteringinto the composition of the granules.

The wetting consists of adding to the pulverulent mixture the variousconstituents, a wetting liquid which may be water, or an aqueous ororganic solution of binder or an alcohol. This is carried out in amixer-kneader of the planetary, roller, projection or whirling type or amixer-granulator of the rapid type.

In step (a), the appropriate wetting liquid is water or an alcohol or anaqueous or organic solution of binder, as generally recommended in theart.

According to a particularly preferred embodiment, theabsorption-promoting agent is used as wetting liquid for thegranulation.

The drying may be carried out in an oven, or in a fluidized air beddryer, or by microwave.

According to a preferred embodiment of the invention, the sizing iscarried out by passing over a screen with a mesh opening of between 0.5and 1.5 mm, preferably between 0.8 and 1.5 mm.

A preferred mesh opening value is 1.25 mm.

However, the invention does not intend to be limited to the use of a wetgranulation method. Thus, persons skilled in the art will also be ableto use other existing granulation methods, such as the dry granulationmethod.

The last step of compression (step d) on an alternating or rotarymachine leads to the formation of the tablet.

The galenic forms of the invention may be provided in the form ofgelatin capsules or any other substitute material, which may bemonolithic, mono- or polyphasic. The content of the gelatin capsule is amatrix of the semisolid type. In this matrix, the active ingredient maybe present in dissolved form or alternatively in suspension. The saidmatrix comprises the absorption-promoting agent described above, theactive ingredient and optionally one or more additional excipientschosen from those described below so as to give the preparation thedesired properties or so as to overcome the disadvantages linked to theprocess of preparing the gelatin capsules.

The additional excipients which may be incorporated into the semisolidmatrix in combination with the mixture of absorption-promoting agentsare of the following categories.

Wetting agents among which are phospholipids such as the derivatives ofphosphatidylcholine or phosphatidylethanolamine better known by the nameof natural or purified lecithins.

Anionic surfactants, such as sodium alkylsulphonates (such as sodiumlauryl sulphate or sodium docusate), cationic surfactants such asquaternary ammoniums (such as benzalkonium chloride or benzethoniumchloride or cetrimide).

Thickening agents of the lipid type, among which are vegetable oils(cotton seed, sesame and groundnut oils) and derivatives of these oils(hydrogenated oils such as hydrogenated castor oil, glycerol behenate).

Thickening agents of the waxy type such as natural carnauba wax ornatural beeswax, synthetic waxes such as cetyl ester waxes.

Thickening agents of the amphiphilic type such as polymers of ethyleneoxide (polyoxyethylene glycol of high molecular weight between 4000 and100000) or propylene and ethylene oxide copolymers (poloxamers).

Thickeners of the cellulosic type (semisynthetic derivatives ofcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxymethylcellulose, of high molecular weight and high viscosity,gum) or any other polysaccharide such as alginic acid.

Thickening agents of the polymeric type such as acrylic acid polymers(such as carbomers).

Thickening agents of the mineral type such as colloidal silica,bentonite.

Antioxidants such as ascorbic acid, ascorbyl palmitate, fumaric acid,sodium ascorbate, sodium metabisulphite.

It will be noted that the thickening agents may be added to the mixtureof promoting agents in an amount of 0.1 per 1 to 10 per 1. The ratiowhich exists between the mixture of promoting agents and the mixture ofthickening agents determines directly, for the same active ingredient,the kinetics of dissolution of the latter.

The monolithic gelatin capsules of the invention are conventionallyprepared by a method including a phase of preparing a semisolid matrixfollowed by casting into a gelatin capsule.

More precisely, the semisolid matrix is prepared by dispersing, withstirring, the active ingredient in the mixture of the variousexcipients. The use of subsidiary heating of the container of mixturemay be necessary in order to maintain this mixture of excipients in aliquid or semi-pasty state until the phase of casting into a gelatincapsule.

Furthermore, it may be envisaged to cast successively in the samegelatin capsule several semisolid matrices, differing from each other bytheir active ingredient and/or excipient compositions, thus makingpossible immediate- and prolonged-type releases which can be adjustedaccording to pharmacokinetic criteria.

Finally, the method of manufacture may be completed, where appropriate,by sealing the gelatin capsule by bandrolling or any other equivalentsystem.

It should also be noted that the gelatin capsule form may be replaced bya soft gelatin capsule form or any other substitute material. All theinformation cited above for the gelatin capsule, both in terms ofcomposition and preparation of the semisolid matrix, remain applicablein this case.

The galenic forms of the invention may be provided in the form ofmicrogranules which may be packaged in a unit dose such as a gelatincapsule, a cachet or a sachet, or even a vial. In this case, themicrogranules are obtained by combining the active ingredient and theabsorption-promoting agent with one or more excipients chosen from thefollowing categories:

Diluents such as calcium carbonate, calcium sulphate dihydrate, sucrose,lactose, dextrates, dextrin, dextrose, dicalcium phosphate dihydrate,kaolin, magnesium carbonate, magnesium oxide, maltodextrin,microcrystalline cellulose, sorbitol, mannitol, starches, talc,tricalcium phosphate.

Thickening agents of the lipid type, among which are vegetable oils(cotton seed, sesame and groundnut oils) and derivatives of these oils(hydrogenated oils such as hydrogenated castor oil, glycerol behenate).

Thickening agents of the waxy type such as natural carnauba wax ornatural beeswax, synthetic waxes such as cetyl ester waxes.

Thickening agents of the amphiphilic type such as polymers of ethyleneoxide (polyoxyethylene glycol of high molecular weight between 4000 and100000) or propylene and ethylene oxide copolymers (poloxamers).

Thickeners of the cellulosic type (semisynthetic derivatives ofcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxymethylcellulose, of high molecular weight and high viscosity,gum) or any other polysaccharide such as alginic acid.

Thickening agents of the polymeric type such as acrylic acid polymers(such as carbomers).

Thickening agents of the mineral type such as colloidal silica,bentonite.

Antioxidants such as ascorbic acid, ascorbyl palmitate, fumaric acid,sodium ascorbate, sodium metabisulphite.

Effervescent mixtures are some of the agents capable of beingincorporated into the microgranules. These mixtures are composed, on theone hand, of alkali or alkaline-earth metal carbonates or sodium glycincarbonate, and, on the other hand, of organic acids such as citric acidor tartaric acid. Polymers of the cellulosic type(hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxymethylcellulose, of high molecular weight and high viscosity) orany other polysaccharide such as alginic acid or of polyacrylic type(carbomers) may also be used in combination. This combination makes itpossible to obtain microgranules having good floatability in biologicalmedia.

These microgranules may be bare, but are preferably film-coated. Thefilm-coating envisaged will make it possible to avoid an unpleasanttaste by bringing about masking of the taste. It may participate inmodifying the release of the active ingredient and/or of the promotingagent. A gastro-resistant film-coating will make it possible to avoidany release in the stomach; a film-coating which is more hydrophobic andinsensitive to pH variations will contribute more towards extending thekinetics of dissolution. Depending on the role attributed to thefilm-coating, persons skilled in the art will be able to choose thefilm-forming agent from among the following categories: cellulosederivatives such as hydroxypropylmethylcellulose, ethyl cellulose,cellulose acetophthalate, cellulose acetopropionate, cellulosetrimelliate, the polymers and copolymers of methacrylic acid and itsderivatives. The film-forming agent will be supplemented with:

plasticizers (such as polyoxyethylene glycols of high molecular weight,esters of polyacids such as citric acid or phthalic acid)

fillers (such as talc, metal oxides such as titanium oxide).

colorants chosen from those usable and approved by the pharmaceuticaland food industries.

The rate of film-coating may vary from 2 to 25% of the weight of thebare microgranules, preferably from 4 to 20% and more preferably from 5to 20%.

Furthermore, it may be envisaged to fill the same gelatin capsule withdifferent types of microgranules, differing from each other by theiractive ingredient and/or absorption-promoting agent and/or excipientcompositions, or to even combine bare and film-coated microgranules,making it possible to adjust the kinetics of release of the activeingredient.

The microgranules are conventionally prepared by a method includingincorporation of the mixture of absorption-promoting agents with thepulverulent mixture of the other excipients and of the activeingredient(s) into a high-speed mixer, followed by nucleation, swellingand spheronization.

As regards the film-coating phase, it is conventionally carried out byspraying a suspension of film-forming agent and additives over a mass ofmoving microgranules in a turbine or more advantageously in a fluidizedair bed apparatus.

The microgranules or a mixture thereof are placed in gelatin capsules inconventional manner using a filling device. For the latter operation,the incorporation of additives such as glidants, lubricants or evendiluents may prove necessary. Persons skilled in the art will be able tochoose either of these compounds from among the excipients cited in thecorresponding paragraphs above.

It should be noted that the microgranules may have a size of between 0.1and 3 mm, preferably between 0.2 and 2 mm and more preferably between0.3 and 1.5 mm.

Furthermore, it is possible to envisage the production of tablets fromthe preceding microgranules. In this case, the cohesion of the tabletscan be ensured by virtue of the addition of other microgranules or of agranule prepared in a conventional manner with the excipientsconventionally used for this purpose.

In order to easily control the kinetics of release of the activeingredient, it is desirable to incorporate one or more of the followingconstituents into the galenic forms of the invention:

glycerol palmitostearate;

a hydrogenated castor oil;

glycerol behenate; or

stearic acid.

The addition of polymeric derivatives may also be envisaged for thispurpose.

As appropriate polymeric substance, there may be mentioned semisyntheticcelluloses of high molecular weight, carbomers such as polyacrylicacids, polymers and copolymers of methacrylic acid and its derivatives.

The examples provided in the remainder of this text illustrate theinvention in greater detail. This will be done with reference to FIGS. 1to 9.

For the sake of simplicity, all the formulations described below have500-mg doses of active ingredient.

In the following examples, the active ingredient is calcium acamprosate(or calcium acetylhomotaurinate) designated ACA in the text whichfollows.

Precirol®) and Precirol ATO5® are glycerol palmitostearate marketed bythe company Gattefosse.

Compritol® is glycerol behenate marketed by the company Gattefosse.

Methocel K15M® is hydroxypropylcellulose marketed by the companyColorcon.

Eudragit RS 30D® is a copolymer of acrylic acid ester and methacrylicacid esters, containing a low content of ammonium groups available fromthe company Rohm.

EXAMPLE 1

Gelatin capsule containing a semisolid matrix providing immediaterelease of the active ingredient.

The constituents for the preparation of the immediate-release semisolidmatrix were used in the following proportions (by weight):

ACA 54% Gélucire 44/14 ® 45% Soya bean lecithin  1%

The excipients are melted at a temperature greater than their meltingpoint, their mixture is homogenized and then the active ingredient isincorporated. The mixture is cast into gelatin capsules of size 00 in asufficient quantity.

EXAMPLE 2

Dissolution profile for the gelatin capsules manufactured according tothe procedure of Example 1.

The dissolution profiles for the gelatin capsules manufactured in thepreceding example were determined after assaying by high-performanceliquid chromatography.

The gelatin capsules to be tested are introduced into reactors whichwere each previously filled with one litre of distilled water, at 37°C., and provided with a temperature regulating system and an efficientstirring system.

During the whole experiment, the reactor is kept stirred at 37° C.

At regular time intervals t, samples of the medium contained in thereactor are collected, filtered on a membrane of porosity 0.45 μm(Millex HA, in cellulose acetate) and analysed by high-performanceliquid chromatography (HPLC) with detection by UV spectrophotometry.

Conditions for analysis by HPLC.

Column having a length of 10 cm and an internal diameter of 4.6 mm,filled with 5-μm particles of octadecylsilylated silica.

Mobile phase: tetrabutylammonium perchlorate solution at 341.9 mg in1000 ml of a water/acetonitrile: 95/5 mixture.

The detection is carried out by UV spectrophotometry at 200 nm.

The quantity q of active ingredient present in the sample is determinedby comparison with the area of the peak obtained under the sameconditions with a reference solution of known concentration. A simplecalculation makes it possible to find the total quantity of activeingredient released into the reactor at the instant t.

The dissolution profile of the gelatin capsule is obtained by plottingon a curve the calculated quantities of active ingredient (expressed inpercentage of the nominal dose) as a function of time. (See FIG. 1).

EXAMPLE 3

Gelatin capsules containing a semisolid matrix providing immediaterelease of the active ingredient.

The table below gives the composition by weight of each of the gelatincapsules.

Gelatin Gelatin Gelatin Gelatin Gelatin Gelatin capsule capsule capsulecapsule capsule capsule Composition 3.1 3.2 3.3 3.4 3.5 3.6 ACA 47% 47%51% 51% 51% 50% Gélucire 39% 39% 30% 28% 25% 30% 44/14 ® Labrasol ® 13%— 18% 20% 23% 18% PEG 400 — 13% — — — — Sorbitan — — — — —  2% trioleateSoya bean  1%  1%  1%  1%  1% — lecithin HLB 14 14 14 14 14 13.5

The procedure is the same as that of Example 1.

EXAMPLE 4

Gelatin capsules containing a semisolid matrix providing prolongedrelease of the active ingredient. The table below gives the compositionby weight of each of the gelatin capsules.

Gelatin capsule Gelatin capsule Composition 4.1 4.2 ACA 54%   54%Gélucire 44/14 ® 32% 22.5% Précirol ® 13% 22.5% Soya bean  1%   1%lecithin

The procedure is the same as that of Example 1.

EXAMPLE 5

Gelatin capsules containing a semisolid matrix providing prolongedrelease of the active ingredient.

The table below gives the composition by weight of each of the gelatincapsules.

Gelatin Gelatin Gelatin Gelatin Gelatin capsule capsule capsule capsulecapsule Composition 5.1 5.2 5.3 5.4 5.5 ACA 54% 54% 54% 54% 54% Gélucire38% 36% 34% 32% 29% 44/14 ® Précirol ®  7%  9% 11% 13% 16% Soya bean  1% 1%  1%  1%  1% lecithin

The procedure is the same as that of Example 1. The dissolution profilesobtained for these gelatin capsules by applying the analytical method ofExample 2 are given in FIG. 2.

EXAMPLE 6

Gelatin capsules containing a semisolid matrix providing prolongedimmediate release of the active ingredient.

Gelatin capsules were filled both with a matrix obtained according toExample 1 and a matrix obtained according to Example 4, gelatin capsule4.5. The weight ratio of the matrix of Example 1 to the matrix ofExample 4 is 1:2.

EXAMPLE 7

Gelatin capsules filled with microgranules for immediate release of theactive ingredient.

The constituents for the preparation of the immediate-releasemicrogranules were used in the following proportions by weight:

Gelatin Gelatin Gelatin Composition capsule 7.1 capsule 7.2 capsule 7.3ACA 50% 75% 85% Gélucire 16% 14% 15% 44/14 ® Lactose 34% 11% —

The pulverulent active ingredient and the excipient are introduced intoa mixer of the rapid type. After the phases of melting of the excipientand then nucleation followed by swelling of the granules, the latter arespheronized.

The dissolution profile obtained for the gelatin capsule 7.2 by applyingthe analytical method of Example 2 is given in FIG. 3.

EXAMPLE 8

Gelatin capsules filled with microgranules for immediate release of theactive ingredient.

The constituents for the preparation of the immediatereleasemicrogranules were used in the following proportions (by weight):

ACA 85% Gélucire 50/13 ® 15%

The method of manufacture which served for the manufacture of themicrogranules of Example 7 was also used in this example.

EXAMPLE 9

Gelatin capsule filled with microgranules for the prolonged release ofthe active ingredient.

The constituents for the preparation of the immediate-releasemicrogranules were used in the following proportions (by weight):

ACA 25% Précirol ® 18% Lactose 57%

The method of manufacture which served for the manufacture of themicrogranules of Example 7 was also used in this example.

The dissolution profile obtained for this gelatin capsule by applyingthe analytical method of Example 2 is given in FIG. 4.

EXAMPLE 10

Gelatin capsules filled with microgranules for the prolonged release ofthe active ingredient.

The constituents for the preparation of the prolonged-releasemicrogranules were used in the following proportions by weight:

Gelatin Gelatin Gelatin Composition capsule 10.1 capsule 10.2 capsule10.3 ACA 75% 75% 75% Gélucire  7% 3.5%   1% 50/13 ® Compritol ®  7%10.5%   13% Lactose 11% 11% 11%

The method of manufacture which served for the manufacture of themicrogranules of Example 7 was also used in this example.

The dissolution profiles obtained for these gelatin capsules by applyingthe analytical method of Example 2 are given in FIG. 5.

EXAMPLE 11

Gelatin capsules filled with microgranules with high floatability.

The constituents for the preparation of these microgranules were used inthe following proportions by weight:

ACA 50%  Gélucire 44/14 ® 9% Précirol ATO 5 ® 9% Methocel K15 M ® 15% Citric ac. 4% Na bicarbonate 8% Lactose 5%

The method of manufacture which served for the manufacture of themicrogranules of Example 7 was also used in this example.

EXAMPLE 12

Gelatin capsules filled with microgranules for the prolonged release ofthe active ingredient.

The constituents for the preparation of the prolonged-releasemicrogranules were used in the following proportions:

ACA 74% Gélucire 44/14 ® 13% Eudragit RS 30D ®  9% Talc  3% Triethylcitrate  1%

The manufacture can be separated into two stages:

The microgranules obtained in Example 7.3 were film-coated using thefollowing suspension of film-forming agent,

Suspension of Eudragit RS 30D ® 250 g Talc 22.50 g Triethyl citrate11.25 g Distilled water 260 g

The film-coating operation is carried out in a fluidized air bedapparatus.

EXAMPLE 13

Gelatin capsules filled with microgranules for the prolonged release ofthe active ingredient.

The constituents for the preparation of the prolonged-releasemicrogranules were used in the following proportions by weight:

Gelatin Gelatin Gelatin Composition capsule 13.1 capsule 13.2 capsule13.3 ACA 80% 74% 66% Gélucire 14% 13% 12% 44/14 ® Ethyl  6% 13% 22%cellulose

The manufacture can be separated into two stages:

The microgranules obtained in Example 7.3 were film-coated using thefollowing suspension of film-forming agent,

Surelease ® (aqueous suspension of ethyl 300 g cellulose) Distilledwater 200 g

The film-coating operation is carried out in a fluidized air bedapparatus.

The dissolution profiles obtained for these gelatin capsules by applyingthe analytical method of Example 2 are given in FIG. 6.

EXAMPLE 14

Gelatin capsules filled with two types of microgranules for theimmediate and prolonged release of the active ingredient.

The constituents for the preparation of the immediate- andprolonged-release microgranules were used in the following proportions:

ACA 78% Gélucire 44/14 ® 14% Ethyl cellulose  8%

The gelatin capsules were prepared by filling with a mixture of baremicrogranules (obtained in Example 7.3) and of the film-coatedmicrogranules (obtained in Example 13.2). The weight ratio of themicrogranules of Example 7.3 to the microgranules of Example 13.2 is40:60.

The dissolution profile obtained for this gelatin capsule by applyingthe analytical method of Example 2 is given in FIG. 7.

EXAMPLE 15

Tablets for the immediate and prolonged release of the activeingredient.

The constituents for the preparation of the tablets for immediate andprolonged release were used in the following proportions by weight:

Tablet Tablet Tablet Tablet Composition 15.1 15.2 15.3 15.4 ACA 50% 50%50% 50% Gélucire 10% 10% 10% 10% 44/14 ® Compritol ® 20% 20% 10% 10%Micro-  9% 14% 19% 24% crystalline cellulose Povidone 10%  5% 10%  5% Mgstearate  1%  1%  1%  1%

The active ingredient is introduced into a rapid mixer-granulator, themolten Gélucire is added with stirring.

Compritol®, povidone and microcrystalline cellulose are then added tothis pulverulent mixture which is subjected to stirring. The wettingliquid, purified water, is then added until well-formed granules andagglomerates are obtained.

The whole is then dried (oven or fluidized air bed) and sized on ascreen with a mesh opening of 1.25 mm.

The dry granule is introduced into a rapid mixed-granulator, and thenmagnesium stearate is added.

The lubricated granule is compressed on a rotary machine equipped, forexample, with oblong dies.

The dissolution profiles obtained for these tablets by applying theanalytical method of Example 2 are given in FIG. 8.

EXAMPLE 16

Tablets for the immediate and prolonged release of the activeingredient.

The constituents for the preparation of these tablets were used in thefollowing proportions by weight:

Composition Bare core ACA 50% Gélucire 44/14 ® 10% Compritol ® 10%Microcrystalline cellulose 19% Povidone 10% Mg stearate  1% Film-coatingHPMC 64% PEG 4000 15% Talc 21%

The method of manufacture comprises two stages. The preparation of thebare cores is carried out as in Example 15; it is followed byfilm-coating in a turbine by spraying a suspension.

EXAMPLE 17

Tablets for the immediate and prolonged release of the activeingredient.

The constituents for the preparation of these tablets were used in thefollowing proportions by weight:

Composition Bare core ACA 47.5% Gélucire 44/14 ® 9.5% Compritol ® 9.5%Microcrystalline cellulose 18% Povidone 9.5% Mg stearate 1% Talc 5%Film-coating HPMC 64% PEG 4000 15% Talc 21%

The method of manufacture comprises two stages. The preparation of thebare cores is carried out as in Example 15; it is followed byfilm-coating in a turbine by spraying a suspension.

The dissolution profile obtained for this tablet by applying theanalytical method of Example 2 is given in FIG. 9.

EXAMPLE 18

Actions of various promoting agents or mixtures of promoting agents onthe permeability of calcium acetylhomotaurinate, in the Caco-2 cellularmodel.

A solution of carbon 14-labelled acamprosate, of known concentration, isplaced in the apical compartment of a Grass Sweetana-type diffusionchamber which comprises a second so-called basolateral compartmentseparated from the first by an insert supporting a monocellularconfluent culture of human colon adenocarcinoma endothelium epithelialcells, Caco-2 line.

Samples are collected at regular intervals from the second basolateralcompartment. The acamprosate concentration is determined byscintigraphy. A simple calculation makes it possible to obtain theapparent permeability coefficient (Papp). The acamprosate solution issupplemented with various promoting agents or mixtures of promotingagents, under varying conditions. The influence of these agents on theapparent permeability coefficient (Papp) was measured. The experimentalresults are grouped together in the following table where the apparentpermeability coefficient values (Papp) are expressed in cm/s.

Action of the absorption-promoting agents: Appearance PermeabilityCoefficient Category of Absorption-Promoting Agent Na glyco Gélucire PEGFatty Ac Labrafil chol- Polysorbate Type None 44/14 37/02 4000 CapricCapryl 1944 cs ate 80 Conc. (% m/v) 0.10 1.0 5.0 1 5 1 5 0.25 0.25 1.05.0 0.2 0.05 0.50 5.0 Papp (10⁻⁷ cm/s Mean (n = 6) 24.0 152.0 618.6 103047.0 55.8 58.5 12.3 63.6 94.3 61.1 206.0 114 27.6 186.0 409.0 Standard1.1 12.9 12.1 216.0 9.2 9.4 30.7 1.2 11.0 17.6 28.4 33.1 11.9 1.8 56.5106.0 deviation

EXAMPLE 19

Increase in the bioavailability of calcium aceylhomotaurinate in Beagledogs by means of an immediate-release oral form.

The relative bioavailability of calcium-acetylhomotaurinate wasdetermined after administration of various immediate-release oralformulations, and in comparison with a reference formulation:gastroresistant tablets at 333 mg.

Protocol:

The study was carried out on 5 dogs of Beagle breed. On the day of theadministration, the dogs, starved from the day before, successivelyreceived at an interval of one week, by the oral route, one of thefollowing galenic forms:

Dose of acamprosate per Number of units Formulation unit (mg)administered Reference formulation (1) 333 2 Reference tablet supple-333 2 mented with 100 mg of sodium glycocholate (2) Gelatin capsule with500 1 semisolid matrix of Example 1 Floating tablet at 500 1 500 mg (3)Immediate-release 500 1 gelatin capsule with micro-granules of Example7.1

(1) Unit composition of the reference tablet 1 Cores Acamprosate 333 mgCrospovidone 10 mg Microcrystalline cellulose 100 mg Magnesium silicate30 mg Starch glycolate 10 mg Colloidal silica 3 mg Magnesium stearate 7mg Film-coating Eudragit L 30D 27.9 mg Talc 6.5 mg Propylene glycol 4.2mg (2) Unit composition of the tablets supplemented with sodiumglycocholate 2 Cores Acamprosate 333 mg Sodium glycocholate 100 mgCrospovidone 10 mg Microcrystalline cellulose 100 mg Magnesium silicate30 mg Starch glycolate 10 mg Colloidal silica 3 mg Magnesium stearate 7mg Film-coating Eudragit L 30D 27.9 mg Talc 6.5 mg Propylene glycol 4.2mg (3) Unit composition of floating tablets at 500 mg. Acamprosate 500mg Hydroxypropylmethylcellulose 550 mg Povidone 80 mg Microcrystallinecellulose 80 mg Sodium bicarbonate 250 mg Talc 7 mg Magnesium stearate 6mg

Blood samples were collected just before the administration, and then0.5; 1; 2; 3; 4; 5; 6; 8 and 24 hours after the administration. Usingthese samples, plasma acamprosate was assayed by gas chromatography/massspectrometry (GC/MS). The following pharmacokinetic parameters were thendetermined for each administered form:

Maximum value of plasma acamprosate (Cmax), area under the curve of theplasma concentrations (AUC), relative bioavailability of the oral formtested (F), established according to the formula:

Dose(reference)×AUC (tested)/F=dose(tested)×AUC(reference)

The mean pharmacokinetic parameters observed for each of the formstested are presented in the table below:

TABLE 1 Mean pharmacokinetic parameters for acamprosate observed inBeagle dogs after single oral administration of variousimmediate-release galenic forms versus the reference form. C max F (ref.Formulation (ng/ml) 666 mg) % Reference formulation 2 17,593 100 tabletsat 333 mg 2 tablets at 333 mg sup-   7921 68 plemented with 100 mg ofsodium glycocholate Gelatin capsule with 16,935 138 semisolid matrix ofExample 1 Floating tablet at 15,072 138 500 mg Immediate-release 19,543146 gelatin capsule with micro-granules of Example 7.1

Conclusion:

The gelatin capsule form containing semisolid matrix of Example 1 andthe immediate-release gelatin capsule form filled with microgranules ofExample 7.1 allow an increase of about 40% in the relativebioavailability of calcium acetylhomotaurinate.

EXAMPLE 20

Increase in the bioavailability of calcuim acetylhomotaurinate in Beagledogs by means of a prolonged-release oral form.

The relative bioavailability of calcium acetylhomotaurinate wasdetermined after administration of various prolonged-release oralformulations, and in comparison with two reference formulations:gastroresistant tablets at 500 mg and a formulation in the form ofimmediate-release gelatin capsules (Example 1). Furthermore, comparisonof the plasma levels at 6 and 24 hours was carried out for all the formstested.

Protocol: The study was carried out on 6 dogs of Beagle breed. On theday of the administration, the dogs, starved from the day before,successively received at an interval of one week, by the oral route, oneof the following galenic forms:

Number of Dose per units Formulation unit (mg) administered Reference 1:gastro resistant 500 2 tablet (1) Reference 2: immediate-release 500 1gelatin capsule with semisolid matrix Example 1 Prolonged-release matrixtablet 500 1 Example 15.3 Prolonged-release gelatin capsule 500 1 withsemisolid matrix Example 4.1 Prolonged-release gelatin capsule 500 1with semisolid matrix Example 4.2 Gelatin capsule with microgranules 5001 Example 14

(1) Unit composition of the gastroresistant 500-mg tablets CoresAcamprosate 500 mg Crospovidone 15 mg Microcrystalline cellulose 150 mgMagnesium silicate 45 mg Starch glycolate 15 mg Colloidal silica 4.5 mgMagnesium stearate 10.5 mg Film-coating Eudragit L 30D 31.1 mg Talc 7.2mg Propylene glycol 4.5 mg

Blood samples were collected just before the administration, and then0.5; 1; 2; 3; 4; 5; 6; 8 and 24 hours after the administration. Usingthese samples, plasma acamprosate was assayed according to an LC/MSmethod. The following pharmacokinetic parameters were then determinedfor each administered form:

Maximum value of plasma acamprosate (Cmax), the plasma levels at 6 hours(C(₆h)) and at 24 hours (C(₂₄h)), area under the curve of the plasmaconcentrations (AUC), relative bioavailability of the oral form tested(F), established according to the formula:$F = \frac{{{Dose}{\quad \quad}({reference})} \times {{AUC}({tested})}}{{dose}\quad ({tested}) \times {{AUC}({reference})}}$

Result:

The mean pharmacokinetic parameters observed for each of the formstested are presented in the table below:

TABLE 2 Mean pharmacokinetic parameters for acamprosate observed inBeagle dogs after single oral administration of various modified-releasegalenic forms versus an immediate form. Cmax Frel. Mean (ng/ml) (%) C (6h) C (24 h) Reference 2: immediate- 20,868 100  3433 69 release gelatincapsule with semisolid matrix Example 1 Gelatin capsule with 12,448 672448 32 microgranules Example 14 Prolonged-release matrix 20,753 99 3916261  tablet Example 15.3 Prolonged-release gelatin 19,175 111  4471 82capsule with semisolid matrix Example 4.1 Prolonged-release gelatin  9363 64 3470 99 capsule with semisolid matrix Example 4.2

Conclusions:

The matrix tablet form (Example 15.3) and the semisolid gelatin capsuleform (Example 4.1) make it possible to maintain or even increase therelative bioavailability of acamprosate, and furthermore the levelsobserved respectively at 6 h and 24 h are greater than those observedfor the reference gelatin capsule: Example 1.

EXAMPLE 21

Evaluation of the relative bioavailability, of the pharmacokineticparameters and of the tolerance of two forms of acamprosate versus thereference form (2×500 mg) after a single administration by the oralroute. Open and crossover studies in 18 healthy male volunteers.

The relative bioavailability of two galenic forms containing 500 mg ofcalcium acetylhomotaurinate was evaluated in men in comparison with areference formulation, also containing 500 mg but of which 2 unit doseswere administered.

Summary of the study:

The following products were randomly administered to 18 healthysubjects, of male sex, of Caucasian origin, aged from 18 to 45 years:

a reference product R: 2 immediate-release gastroresistant tabletscontaining 500 mg doses (on an empty stomach).

a so-called “floating” tablet F containing a 500 mg dose (not on anempty stomach).

a gelatin capsule G with semisolid matrix containing a 500 mg dose:Example 1 (on an empty stomach).

Unit composition of the 500 mg gastroresistant tablets: R CoresAcamprosate 500 mg Crospovidone 15 mg Microcrystalline cellulose 150 mgMagnesium silicate 450 mg Starch glycolate 15 mg Colloidal silica 4.5 mgMagnesium stearate 10.5 mg Film-coating Eudragit L 30D 31.1 mg Talc 7.2mg Propylene glycol 4.5 mg Unit composition of the floating tablets at500 mg: F Acamprosate 500 mg Hydroxypropylmethylcellulose 550 mgPovidone 80 mg Microcrystalline cellulose 80 mg Sodium bicarbonate 250mg Citric acid 100 mg Talc 7 mg Colloidal silica 3.2 mg Magnesiumstearate 6 mg

Blood samples were collected at the following times:

0-0.5-1-1.5-2-3-4-5-6-8-10 -12-14-16-24-36-48 and 72 hours.

The samples were assayed according to a method by gas-liquidchromatography coupled to mass spectrometry with detection by massfragmentometry.

Using the plasma values obtained, the following variables werecalculated:

the area under the curve (AUC),

the maximum plasma concentration (C_(max),)

the time for obtaining the maximum plasma concentration (T_(max)) ofacamprosate.

The relative bioavailability (F) obtained using the following equation:$F = \frac{{{Dose}{\quad \quad}({reference})} \times {{AUC}({tested})}}{{dose}\quad ({tested}) \times {{AUC}({reference})}}$

Results:

All the pharmacokinetic parameters observed for the mean kinetic valuesare presented in Table 3:

TABLE 3 Mean pharmacokinetic parameters observed after after a singleoral administration of various immediate oral forms of acamprosate to 16young healthy volunteers. Mean Dose Tmax Cmax C24 F CV % mg (h) (ng/ml)(ng/ml) (%) Reference 1000  4.3 248 60 100 R Floating tablet 500 3.4 27828 121 F Gelatin capsule 500 1.1 1725  29 274 G

Conclusion:

The formulation in the form of a gelatin capsule with semisolid matrixmakes it possible to obtain a larger plasma peak which indicatespotentiation of the absorption which thereby causes an increase inbioavailabilitity by a factor of 2.74 relative to a formulation in theform of a conventional gastroresistant tablet.

What is claimed is:
 1. An orally administerable galenic formulationallowing improved absorption by the transmembrane or paracellular routein the gastrointestinal tract, comprising at least one active ingredientwhich is a guanidine or a guanylguanidine, an absorption-promoting agenthaving an HLB greater than 8 which is one or more lipid substancesselected from polysorbates, ethers of polyoxyethylene and alkyl, estersof polyoxyethylene and fatty acids, fatty acids, fatty alcohols, bileacids and their salts with pharmaceutically acceptable cations, estersof C₁-C₆ alkanols with fatty acids, esters of polyol with fatty acids,wherein said polyol comprises 2 to 6 hydroxyl functional groups, andpolyglycolysed glycerides, and one or more pharmaceutically acceptableexcipients.
 2. The galenic formulation according to claim 1, furthercomprising an active ingredient which is hydrophilic or ionizable inphysiological media which comprises at least one functional group chosenfrom carboxylic acid, sulphonic acid, phosphonic acid, phosphoric acid,phosphinic acid and phenol functional groups in free form or ionizedform with pharmacologically acceptable cations.
 3. The galenicformulation according to claim 2, wherein the active ingredient which ishydrophilic or ionizable in physiological media comprises at least onefunctional group chosen from sulphonic acid, phosphoric acid, phosphinicacid and phosphinic acid functional groups in free form or ionized formwith pharmacologically acceptable cations.
 4. The galenic formulationaccording to claim 1, comprising an active ingredient in the form of acalcium salt.
 5. The galenic formulation according to claim 1, whereinthe active ingredient, free or in ionized form with the cations or theanions present, has a solubility greater than 100 g/l.
 6. The galenicformulation according to claim 5, wherein said active ingredient free orin its ionized form with the cations or the anions present has apartition coefficient D (octanol/water) corresponding to therelationship log₁₀D<−0.5.
 7. The galenic formulation according to claim1, wherein an active ingredient is contained of the formula:

in which X is

R is a C₁-C₇ alkyl radical, R₁, R₂, R₃ are hydrogen or a C₁-C₇ alkylradical, A is a group of the formula:

v and w=0, 1, 2, independently, or A is a group of formula

R₅, R₆, independently of each other, are hydrogen, C₁-C₇ alkyl, an arylradical having from 6 to 14 carbon atoms, or a heteroaryl radical whichfuryl, thienyl or thiazolyl, it being possible for the aryl andheteroaryl radicals to carry 1 to 3 substituents which are C₁-C₇ alkyl,halogen or trifluoromethyl, and t=1-3, R₄ is hydrogen, C₁-C₇ alkyl, CF₃,aryl having from 6 to 14 carbon atoms, heteroaryl which is furyl,thienyl, or thiazolyl, it being possible for the aryl and heteroarylradicals to carry 1 to 3 substituents which are C₁-C₇ alkyl, halogen ortrifluoromethyl, M represents a monovalent metal (Na, K, Li) or adivalent metal (Ca, Mg, Sr, Zn), m=1 or 2, p=1-2 and q=1-2, p and qbeing such that the electrical neutrality of the salt is ensured.
 8. Thegalenic formulation according to claim 7, wherein an active ingredienthas the formula (I) in which


9. The galenic formulation according to claim 7, wherein an activeingredient has the formula (I) in which


10. The galenic formulation according to claim 7, wherein an activeingredient which is hydrophilic or ionizable in physiological media ofFormula I is calcium acamprosate.
 11. The galenic formulation accordingto claim 1, wherein the active ingredient which is a guanidine or aguanylguanidine is metformin or one of its pharmaceutically acceptablesalts.
 12. The galenic formulation according to claim 1, wherein theabsorption-promoting agent has an HLB greater than
 10. 13. The galenicformulation according to claim 1, wherein the polyol esters with fattyacids are esters of glycols, esters of polyglycerols, esters oranhydrides of sorbitol.
 14. The galenic formulation according to claim1, wherein the absorption-promoting agent comprises at least onepolyglycolyzed glyceride having an HLB of between 12 and
 16. 15. Thegalenic formulation according to claim 1, wherein theabsorption-promoting agent comprises at least one polyglycolyzedglyceride and a sorbitan ester with one or more fatty acids.
 16. Thegalenic formulation according to claim 15, wherein theabsorption-promoting agent comprises a mixture of one or morepolyglycolyzed glycerides and a sorbitan ester with a saturated orunsaturated C₈-C₂₂ fatty acid.
 17. The galenic formulation according toclaim 1, wherein the weight ratio of the active ingredient to theabsorption-promoting agent is between 0.001 and
 10. 18. The galenicformulation according to claim 17, which is a tablet wherein the weightratio of the active ingredient to the absorption-promoting agent isbetween 1 and
 10. 19. The galenic formulation according to claim 17,which is a gelatin capsule wherein the weight ratio of the activeingredient to the absorption-promoting agent is between 0.1 and
 2. 20.The galenic formulation according to claim 1, further comprising anagent allowing the control of the kinetics of release of the activeingredient chosen from glycerol palmitostearates, glycerol behenates,hydrogenated castor oils and mixtures thereof.
 21. A method forimproving the absorption by the transmembrane or paracellular route inthe gastrointestinal tract of active ingredients which are hydrophilicor ionizable in physiological media, comprising administering anabsorption-promoting agent in the form of an orally administerablepharmaceutical formulation according to claim
 1. 22. The methodaccording to claim 21, wherein the active ingredient which ishydrophilic or ionizable in physiological media comprises at least onefunctional group which is carboxylic acid, sulphonic acid, phosphinicacid, phosphoric acid, phosphinic acid or phenol functional groups infree form or ionized with pharmaceutically acceptable cations.
 23. Themethod according to claim 21, wherein the weight ratio of the activeingredient to the absorption-promoting agent is between 0.01 and
 10. 24.The method of preparing a galenic formulation according to claim 1 inthe form of a tablet, comprising (i) preparing by the wet route, agranule of an active substance form a pulverulent mixture of the activesubstance and various excipients, and (ii) compressing, wherein theabsorption-promoting agent used in (i) acts as a wetting liquid.
 25. Thegalenic form according to claim 5, wherein the active ingredient has asolubility greater than 250 g/l.
 26. The galenic form according to claim6, wherein the active ingredient, free or in its ionized form with acation or anion present, has a partition coefficient D (octanol/water)corresponding to the relationship log₁₀D<−20.
 27. The galenic formaccording to claim 12, wherein the absorption-promoting agent has an HLBbetween 12 and
 16. 28. The galenic form according to claim 16, whereinthe absorption-promoting agent comprises a mixture of one or morepolyglycolyzed glycerides and a sorbitan ester with a saturated orunsaturated C₁₀-C₁₄ fatty acid.